Reconciling high-throughput gene essentiality data with metabolic network reconstructions

PLoS Comput Biol. 2019 Apr 11;15(4):e1006507. doi: 10.1371/journal.pcbi.1006507. eCollection 2019 Apr.

Abstract

The identification of genes essential for bacterial growth and survival represents a promising strategy for the discovery of antimicrobial targets. Essential genes can be identified on a genome-scale using transposon mutagenesis approaches; however, variability between screens and challenges with interpretation of essentiality data hinder the identification of both condition-independent and condition-dependent essential genes. To illustrate the scope of these challenges, we perform a large-scale comparison of multiple published Pseudomonas aeruginosa gene essentiality datasets, revealing substantial differences between the screens. We then contextualize essentiality using genome-scale metabolic network reconstructions and demonstrate the utility of this approach in providing functional explanations for essentiality and reconciling differences between screens. Genome-scale metabolic network reconstructions also enable a high-throughput, quantitative analysis to assess the impact of media conditions on the identification of condition-independent essential genes. Our computational model-driven analysis provides mechanistic insight into essentiality and contributes novel insights for design of future gene essentiality screens and the identification of core metabolic processes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computational Biology
  • Culture Media
  • DNA Transposable Elements
  • Databases, Genetic / statistics & numerical data
  • Genes, Essential*
  • Genome, Bacterial
  • High-Throughput Nucleotide Sequencing / statistics & numerical data
  • Humans
  • Metabolic Networks and Pathways / genetics*
  • Models, Genetic
  • Mutagenesis
  • Pseudomonas aeruginosa / genetics
  • Pseudomonas aeruginosa / growth & development
  • Pseudomonas aeruginosa / metabolism

Substances

  • Culture Media
  • DNA Transposable Elements

Grant support

Support for this project was provided by The Wagner Fellowship (ASB) and Unilever (ASB and JAP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.